The present invention relates to new aza-indolyl derivatives, to processes and intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The active compounds of the present invention are useful in treating obesity and other disorders.
It has been recognized that obesity is a disease process influenced by environmental factors in which the traditional weight loss methods of dieting and exercise need to be supplemented by therapeutic products (S. Parker, xe2x80x9cObesity: Trends and Treatmentsxe2x80x9d, Scrip Reports, PJB Publications Ltd, 1996).
Whether someone is classified as overweight or obese is generally determined on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m2). Thus, the units of BMI are kg/m2 and it is possible to calculate the BMI range associated with minimum mortality in each decade of life. Overweight is defined as a BMI in the range 25-30 kg/m2, and obesity as a BMI greater than 30 kg/m2. There are problems with this definition in that it does not take into account the proportion of body mass that is muscle in relation to fat (adipose tissue). To account for this, obesity can also be defined on the basis of body fat content: greater than 25% and 30% in males and females, respectively. Using BMI and/or other conventional diagnosis tools, prescribing doctors are well able to determine which of their patients are in need of treatment for obesity.
As the BMI increases there is an increased risk of death from a variety of causes that is independent of other risk factors. The most common diseases with obesity are cardiovascular disease (particularly hypertension), diabetes (obesity aggravates the development of diabetes), gall bladder disease (particularly cancer) and diseases of reproduction. Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.
Compounds marketed as anti-obesity agents include Orlistat (XENICAL(copyright)) and Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorption directly and tends to produce a high incidence of unpleasant (though relatively harmless) side-effects such as diarrhoea. Sibutramine (a mixed 5-HT/noradrenaline reuptake inhibitor) can increase blood pressure and heart rate in some patients. The serotonin releaser/reuptake inhibitors fenfluramine (Pondimin(copyright)) and dexfenfluramine (Redux(trademark)) have been reported to decrease food intake and body weight over a prolonged period (greater than 6 months). However, both products were withdrawn after reports of preliminary evidence of heart valve abnormalities associated with their use. There is therefore a need for the development of a safer anti-obesity agent.
The non-selective 5-HT2C receptor agonists/partial agonists m-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine (TFMPP) have been shown to reduce food intake in rats (G. A. Kennett and G. Curzon, Psychopharmacol., 1988, 96, 93-100; G. A. Kennett, C. T. Dourish and G. Curzon, Eur. J. Pharmacol., 1987, 141, 429-435) and to accelerate the appearance of the behavioural satiety sequence (S. J. Kitchener and C. T. Dourish, Psychopharmacol., 1994, 113, 369-377). Recent findings from studies with mCPP in normal human volunteers and obese subjects have also shown decreases in food intake. Thus, a single dose of mCPP decreased food intake in female volunteers (A. E. S. Walsh et al., Psychopharmacol., 1994, 116, 120-122) and decreased the appetite and body weight of obese male and female subjects during subchronic treatment for a 14 day period (P. A. Sargeant et al., Psychopharmacol., 1997, 133, 309-312). The anorectic action of mCPP is absent in 5-HT2C receptor knockout mutant mice (L. H. Tecott et al., Nature, 1995, 374, 542-546) and is antagonised by the 5-HT2C receptor antagonist SB-242084 in rats (G. A. Kennett et al., Neuropharmacol., 1997, 36, 609-620). It seems therefore that mCPP decreases food intake via an agonist action at the 5-HT2C receptor.
Other compounds which have been proposed as 5-HT2C receptor agonists for use in the treatment of obesity include the substituted 1-aminoethyl indoles disclosed in EP-A-0655440. CA-2132887 and CA-2153937 disclose that tricyclic 1-aminoethylpyrrole derivatives and tricyclic 1-aminoethyl pyrazole derivatives bind to 5-HT2C receptors and may be used in the treatment of obesity. WO-A-98/30548 discloses aminoalkylindazole compounds as 5-HT2C agonists for the treatment of CNS diseases and appetite regulation disorders. 2-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)ethylamine is disclosed in J.Med.Chem., 1965, 8, 700. The preparation of pyrido[1,2-a]indoles for the treatment of cerebrovascular disorders is disclosed in EP-A-0252643 and EP-A-0167901. The preparation of 10-[(acylamino)ethyl]tetrahydropyrido[1,2-a]indoles as anti-ischemic agents is disclosed in EP-A-0279125.
It is an object of this invention to provide selective, directly acting 5HT2 receptor ligands for use in therapy and particularly for use as anti-obesity agents. It is a further object of this invention to provide directly acting ligands selective for 5-HT2B and/or 5-HT2C receptors, for use in therapy and particularly for use as anti-obesity agents. It is a further object of this invention to provide selective, directly acting 5-HT2C receptor ligands, preferably 5-HT2C receptor agonists, for use in therapy and particularly for use as anti-obesity agents.
According to the present invention there is provided a chemical compound of formula (I): 
wherein
n is 1, 2 or 3;
X1 is nitrogen or CR4; X2 is nitrogen or CR5; X3 is nitrogen or CR6; X4 is nitrogen or CR7; wherein one or two of X1, X2, X3 and X4 are nitrogen;
R1, R2 and R3 are independently selected from hydrogen and alkyl;
R4, R5, R6 and R7 are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxyl, alkylsulfonyl, arylsulfoxyl, arylsulfonyl, amino, monoalkylamino, dialkylamino, nitro, cyano, carboxaldehyde, alkylcarbonyl, arylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylamino and dialkylaminocarbonylamino, and wherein a carbon ring atom next to a nitrogen is not substituted by halogen;
and pharmaceutically acceptable salts and prodrugs thereof. Preferred are the compounds according to formula (I) and salts thereof.
As used herein, the term xe2x80x9calkylxe2x80x9d means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical. Where cyclic, the alkyl group is preferably C3 to C12, more preferably C5 to C10, more preferably C5, C6 or C7. Where acyclic, the alkyl group is preferably C1 to C10, more preferably C1 to C6, more preferably methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl), more preferably methyl.
As used herein, the term xe2x80x9clower alkylxe2x80x9d means methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl). Preferably, these lower alkyl groups are unsubstituted.
As used herein, the term xe2x80x9carylxe2x80x9d means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more, preferably one, heteroatom, such as pyridyl, pyrrolyl, furanyl and thienyl.
The alkyl and aryl groups may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents may include:
carbon-containing groups such as
alkyl,
aryl,
arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl);
halogen atoms and halogen-containing groups such as
haloalkyl (e.g. trifluoromethyl);
oxygen-containing groups such as
alcohols (e.g. hydroxy, hydroxyalkyl, aryl(hydroxy)alkyl),
ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl),
aldehydes (e.g. carboxaldehyde),
ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl),
acids (e.g. carboxy, carboxyalkyl),
acid derivatives such as esters (e.g. alkoxycarbonyl, alkoxycarbonylalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl),
amides (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl, aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl, arylaminocarbonyl),
carbamates (e.g. alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, arylaminocarbonyloxy)
and ureas (e.g. mono- or di-alkylaminocarbonylamino or arylaminocarbonylamino);
nitrogen-containing groups such as
amines (e.g. amino, mono- or di-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl),
azides,
nitriles (e.g. cyano, cyanoalkyl),
nitro;
sulfur-containing groups such as
thiols, thioethers, sulfoxides and sulfones (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl);
and heterocyclic groups containing one or more, preferably one, heteroatom, (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl and carbolinyl).
As used herein, the term xe2x80x9calkoxyxe2x80x9d means alkyl-Oxe2x80x94 and xe2x80x9calkoylxe2x80x9d means alkyl-COxe2x80x94. Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by one or more alkyl groups.
As used herein, the term xe2x80x9chalogenxe2x80x9d means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical.
As used herein the term xe2x80x9cprodrugxe2x80x9d means any pharmaceutically acceptable prodrug of the compound of formula (I).
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d or xe2x80x9csaltxe2x80x9d means any pharmaceutically acceptable salt of the compound of formula (I). Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are fumaric, hydrochloric, hydrobromic, phosphoric, succinic, sulfuric and methanesulfonic acids. Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
The term xe2x80x9clipase inhibitorxe2x80x9d refers to compounds that are capable of inhibiting the action of lipases, for example gastric and pancreatic lipases. For example orlistat and lipstatin as described in U.S. Pat. No. 4,598,089 are potent inhibitors of lipases. Lipstatin is a natural product of microbial origin, and orlistat is the result of a hydrogenation of lipstatin. Other lipase inhibitors include a class of compounds commonly referred to as panclicins. Panclicins are analogues of orlistat (Mutoh et al, 1994). The term xe2x80x9clipase inhibitorxe2x80x9d refers also to polymer bound lipase inhibitors for example described in International Patent Application WO99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterised in that they have been substituted with one or more groups that inhibit lipases. The term xe2x80x9clipase inhibitorxe2x80x9d also comprises pharmaceutically acceptable salts of these compounds. The term xe2x80x9clipase inhibitorxe2x80x9d preferably refers to orlistat.
Orlistat is a known compound useful for the control or prevention of obesity and hyperlipidemia. See, U.S. Pat. No. 4,598,089, issued Jul. 1, 1986, which also discloses processes for making orlistat and U.S. Pat. No. 6,004,996, which discloses appropriate pharmaceutical compositions. Further suitable pharmaceutical compositions are described for example in International Patent Applications WO 00/09122 and WO 00/09123. Additional processes for the preparation of orlistat are disclosed in European Patent Applications Publication Nos. 185,359, 189,577, 443,449, and 524,495.
Orlistat is preferably orally administered from 60 to 720 mg per day in divided doses two to three times per day. Preferred is wherein from 180 to 360 mg, most preferably 360 mg per day of a lipase inhibitor is administered to a subject, preferably in divided doses two or, particularly, three times per day. The subject is preferably an obese or overweight human, i.e. a human with a body mass index of 25 or greater. Generally, it is preferred that the lipase inhibitor be administered within about one or two hours of ingestion of a meal containing fat. Generally, for administering a lipase inhibitor as defined above it is preferred that treatment be administered to a human who has a strong family history of obesity and has obtained a body mass index of 25 or greater.
Orlistat can be administered to humans in conventional oral compositions, such as, tablets, coated tablets, hard and soft gelatin capsules, emulsions or suspensions. Examples of carriers which can be used for tablets, coated tablets, dragees and hard gelatin capsules are lactose, other sugars and sugar alcohols like sorbitol, mannitol, maltodextrin, or other fillers; surfactants like sodium lauryl sulfate, Brij 96, or Tween 80; disintegrants like sodium starch glycolate, maize starch or derivatives thereof; polymers like povidone, crospovidone; talc; stearic acid or its salts and the like. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Moreover, the pharmaceutical preparations can contain preserving agents, solubilizers, stabilising agents, wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for varying the osmotic pressure, buffers, coating agents and antioxidants. They can also contain still other therapeutically valuable substances. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods known in the pharmaceutical art. Preferably, orlistat is administered according to the formulation shown in the Examples and in U.S. Pat. No. 6,004,996, respectively.
In a preferred embodiment the present invention refers to compounds as defined above wherein in case two of X1, X2, X3 and X4 are nitrogen these nitrogen atoms are in meta or para position to each other.
In a preferred embodiment the present invention refers to compounds as defined above wherein X1 is nitrogen, X2 is CR5, X3 is CR6, and X4 is CR7.
In a further preferred embodiment the present invention refers to compounds as defined above wherein X1 is CR4; X2 is nitrogen; X3 is CR6 and X4 is CR7.
In a further preferred embodiment the present invention refers to compounds as defined above wherein X1 is CR4, X2 is CR5; X3 is nitrogen and X4 is CR7.
In a further preferred embodiment the present invention refers to compounds as defined above wherein X1 is CR4, X2 is CR5; X3 is CR6 and X4 is nitrogen.
In a further preferred embodiment the present invention refers to compounds as defined above wherein X1 is nitrogen, X2 is CR5, X3 is nitrogen and X4 is CR7.
In a further preferred embodiment the present invention refers to compounds as defined above wherein X1 is CR4, X2 is nitrogen, X3 is CR6 and X4 is nitrogen.
In a further preferred embodiment the present invention refers to compounds as defined above wherein X1 is nitrogen, X2 is CR5, X3 is CR6 and X4 is nitrogen.
In a preferred embodiment, the compounds of formula (I) are selected from compounds in which n is 1.
Preferably, the compounds of formula (I) are selected from compounds in which R1 is the same as R2. Preferably, R1 and R2 are both hydrogen. In a preferred embodiment of the invention, R1 is hydrogen and R2 is alkyl (preferably lower alkyl and more preferably methyl) optionally substituted by an aryl (preferably a substituted or unsubstituted phenyl or thienyl group) or by a cycloalkyl group (preferably saturated and preferably selected from a C3, C4, C5, C6 and C7 cycloalkyl group).
Preferably, the compounds of formula (I) are selected from compounds in which R3 is lower alkyl, preferably methyl or ethyl, preferably methyl.
R4 to R7 are independently selected from hydrogen, halogen, hydroxy, alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl) and arylalkyl), aryl, alkoxy (including arylalkoxy), aryloxy, alkylthio, arylthio, alkylsulfoxyl, alkylsulfonyl, arylsulfoxyl, arylsulfonyl, amino, monoalkylamino, dialkylamino, nitro, cyano, carboxaldehyde, alkylcarbonyl, arylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylamino and dialkylaminocarbonylamino.
In an embodiment of the invention, R4 to R7 are independently selected from hydrogen, halogen, hydroxy, alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl) and arylalkyl), aryl, alkoxy (including arylalkoxy), aryloxy, alkylthio, alkylsulfoxyl and alkylsulfonyl.
It is preferred that R4 is selected from hydrogen and halogen, preferably hydrogen.
It is preferred that R5 is selected from a substituent group other than hydrogen, and preferably from halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, monoalkylamino and dialkylamino, and more preferably from halogen (preferably fluoro, chloro and bromo), alkyl (preferably lower alkyl and preferably trifluoromethyl), alkoxy (preferably lower alkoxy) and alkylthio (preferably lower alkylthio).
It is preferred that R6 is selected from halogen (preferably fluoro and chloro) and hydrogen. In an embodiment of the invention, R6 is a substituent group other than hydrogen.
In an embodiment of the invention, two or three of R4, R5, R6 and R7, preferably two or three of R4, R6 and R7 are hydrogen.
In a most preferred embodiment of the invention, one of X1, X2, X3 and X4 is nitrogen and the rest are CH; R1, R2 and R3 are H or lower alkyl and n is 1 or 2. Compounds according to this most preferred embodiment include: (R,S)-2-(2,3-dihydro-1H-3a,6-diaza-cyclopenta[a]inden-8-yl)-1-methyl-ethylamine; (R,S)-2-(2,3-dihydro-1 H-3a,4-diaza-cyclopenta[a]inden-8-yl)-1-methyl-ethylamine; (R,S)-2-(2,3-Dihydro-1H-3a,5-diaza-cyclopenta[a]inden-8-yl)-1-methyl-ethylamine; 2-(2,3-dihydro-1H-3a,6-diaza-cyclopenta[a]inden-8-yl)-ethylamine and isolated enantiomers thereof.
Where the compounds of formula (I) are in salt form, the fumarate salts are preferred.
The compounds of the invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. The compounds can be, for example, racemates or optically active forms. The optically active forms can be obtained by resolution of the racemates or by asymmetric synthesis.
According to a further aspect of the invention, there is provided a compound of formula (I) for use in therapy.
The compounds of formula (I) may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT2 receptor function. The compounds may act as receptor agonists or antagonists. Both agonists and antagonists are useful in treating disorders associated with 5-HT2 receptor function, depending on whether the disorder is associated with insufficient or excessive 5-HT2 receptor function. Whether any particular compound of formula (I) is an agonist or antagonist can be determined by the xe2x80x9cFunctional activityxe2x80x9d assay taught in the Experimental section below. Preferably, the compounds may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT2B and/or 5-HT2C receptor function. Preferably, the compounds may be used in the treatment (including prophylactic treatment) of disorders where a 5-HT2C receptor agonist is required, such as obesity.
The compounds of formula (I) may be used in the treatment or prevention of central nervous disorders such as depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioural disorders, behavioural disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, anorexia nervosa or premenstrual tension; damage of the central nervous system such as by trauma, stroke, neurodegenerative diseases or toxic or infective CNS diseases such as encephalitis or meningitis; cardiovascular disorders such as thrombosis; gastrointestinal disorders such as dysfunction of gastrointestinal motility; diabetes insipidus; and sleep apnea.
According to a further aspect of the invention, there is provided use of a compound of formula (I) in the manufacture of a medicament for the treatment (including prophylaxis) of the above-mentioned disorders. In a preferred embodiment, there is provided use of a compound of formula (I) in the manufacture of a medicament for the treatment (including prophylaxis) of obesity. The term obesity includes eating disorders.
According to a further aspect of the invention, there is provided a method of treatment (including prophylaxis) of a disorder selected from the group consisting of the above-mentioned disorders comprising administering to a patient in need of such treatment an effective dose of a compound of formula (I). In a preferred embodiment, there is provided a method of treatment (including prophylaxis) of obesity.
According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of formula (I) with a pharmaceutically acceptable carrier or excipient.
According to a further aspect of the invention, there is provided a method of preparing a compound of formula (I), especially a method comprising reduction and/or reductive alkylation of a compound of formula (VI) 
wherein X1, X2, X3, X4, R3 and n are as defined above.
The compounds of formula I can contain several asymmetric centres and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbens or eluant).
The term xe2x80x9casymmetric carbon atom (C*)xe2x80x9d means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog-Convention the asymmetric carbon atom can be of the xe2x80x9cRxe2x80x9d or xe2x80x9cSxe2x80x9d configuration.
Preferred are chiral compounds of formula (I), wherein R1 to R3, X1 to X4 and n are defined as before. Particularly preferred are compounds according to formula (Ib) 
wherein R1 to R3, X1 to X4 and n are defined as before. Formula (Ib) means that the asymmetric carbon atom C* 
is of the R configuration.
A further particularly preferred aspect of the present invention are compounds according to formula (Ia) 
wherein R1 to R3, X1 to X4 and n are defined as before. Formula (Ia) means that the asymmetric carbon atom C* 
is of the S configuration.
Likewise preferred are compounds of formula I, wherein R3 is hydrogen.
Particularly preferred are compounds of formula I selected from the following compounds:
(S)-2-(2,3-dihydro-1H-3a,5-diaza-cyclopenta[a]inden-8-yl)-1-methyl-ethylamine;
(R)-2-(2,3-dihydro-1H-3a,5-diaza-cyclopenta[a]inden-8-yl)-1-methyl-ethylamine;
(S)-2-(2,3-dihydro-1H-3a,6-diaza-cyclopenta[a]inden-8-yl)-1-methyl-ethylamine;
(R)-2-(2,3-dihydro-1H-3a,6-diaza-cyclopenta[a]inden-8-yl)-1-methyl-ethylamine;
and 2-(2,3-dihydro-1H-3a,6-diaza-cyclopenta[a]inden-8-yl)-ethylamine.
Another preferred aspect of the invention is a method of treatment of obesity in a human in need of such treatment which comprises administration to the human a therapeutically effective amount of a compound of the present invention and a therapeutically effective amount of a lipase inhibitor. Particularly preferred is this method of treatment, wherein the lipase inhibitor is orlistat.
Further preferred is the use of a compound of the present invention in the manufacture of a medicament for the treatment and prevention of obesity in a patient who is also receiving treatment with a lipase inhibitor. Particularly preferred is this use, wherein the lipase inhibitor is orlistat.
Another preferred aspect is the pharmaceutical composition, as above, further comprising a therapeutically effective amount of a lipase inhibitor. Particularly preferred is this pharmaceutical composition, wherein the lipase inhibitor is orlistat.
Compounds of the invention may be prepared according to Reaction Scheme 1 below. R1 to R7 are as previously defined.
Compounds of formula (II) may be prepared by reaction of the corresponding protected amine with iodine (I2, nBuLi, TMEDA) and deprotection of the amino group. The corresponding amines are available commercially or has been described in the literature for many combinations of X1, X2, X3 and X4, such as amino-pyridino, amino-pyrimidino and amino-pyrazine derivatives, and the introduction of an amino-protecting group can be performed by conventional methods. Some starting compounds in which one or more X is CR where R is not hydrogen are also commercially available, e.g. with methoxy or halogen substituents. Conversion of such an R group into another desired substituent, for instance into hydroxy, can also be performed by conventional methods. All possible starting reactants for Scheme I meeting the definitions of X1, X2, X3 and X4 from formula (I) can be prepared by conventional methods from commercially available starting materials or compounds described in the literature.
Compounds of formula (II) may be reacted with compounds of formula (III) under palladium catalysed conditions to give compounds of formula (IV). Alkynes such as compounds of the formula (III) are well-described in the literature and the compounds of formula (III) can be derived from commercially available materials by conventional methods. The carboxaldehyde (V) may be obtained by reaction of compound (IV) with e.g. the Vilsmeier reagent prepared from DMF and phosphorus oxychloride under standard conditions. The nitroalkene (VI) may be obtained by reaction of compound (V) with a nitroalkane. Compounds of formula (I) can be formed in the reaction of the nitroalkene (VI) with a reducing agent such as lithium aluminium hydride in an ethereal solvent. 
The compounds of formula (I) (R1 and/or R2=alkyl) may be prepared from compounds of formula (I) (R1=R1=H) by standard methods such as reductive alkylation with an appropriate aldehyde or ketone in the presence of a reducing agent such as sodium triacetoxcyborohydride, formic acid or sodium cyanoborohydride.
According to a further aspect of the invention there is provided a method of preparing compounds of formula (I), especially in enantiomerically pure form shown in formula (Ic). See Scheme 2. The intermediate (IV) is halogenated, perferably brominated or iodinated with suitable halogenating reagents agents (e.g. bromine or N-Iodosuccinimide in an inert solvent e.g. dimethylformamide or acetonitrile) to yield an intermediate of formula (VII). This intermediate (VII) is treated with an agent effecting halogen-metal exchange, preferably halogen-lithium exchange (e.g. with butyl-lithium in an inert solvent e.g. THF) and treated with the novel chiral Sulfamidate A to yield an intermediate of formula (VIII). This latter intermediate (VIII) is transformed to a compound of formula (I) by methods known in the art, particularly by acid mediated cleavage of the BOC (meaning tert-butlyoxycarbonyl) protecting group. Particularly preferred acids are trifluoroacetic acid or mixtures of trifluoroacetic acid in inert solvents such as dichloromethane and solutions of hydrochloric acid in inert solvents such as ethyl acetate, dioxane or diethyl ether. The stereochemistry, as indicated by the star (*), present in the chiral Sulfamidates A is without loss of integrity transferred onto the intermediates (VIII) and compounds (I). 
The novel sulfamidates of type A are conveniently obtained from commercially available BOC protected alpha amino alcohols, in particular BOC-glycinol, BOC-D-alalinol and BOC-L-alalinol, by first reacting with thionylchloride in an inert solvent such as tetrahydrofurane dichloromethane or ethyl acetate in the presence of a suitable base such as n-butyl lithium, triethylamine, imidazole or pyridine and the like and oxidizing the intermediate Sulfamidite B with suitable oxidizing agents such as sodium metaperiodate in the presence of suitable catalysts such as rutheniumdioxide hydrate. The stereochemistry, as indicated by the star (*), present in the BOC protected alpha amino alcohols is without loss of integrity transferred onto the intermediates B and compounds A. 
If, in any of the processes mentioned herein, the substituent group R4, R5, R6 or R7 is other than the one required, the substituent group may be converted to the desired substituent by known methods. The substituents R4, R5, R6 or R7 may also need protecting against the conditions under which the reaction is carried out. In such a case, the protecting group may be removed after the reaction has been completed.
The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from basic compounds.
The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) transdermal or rectal administration or in a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.
The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., obesity) is 0.1 to 500 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
The invention will now be described in detail with reference to the following examples. It will be appreciated that the invention is described by way of example only and modification of detail may be made without departing from the scope of the invention.
Binding to Serotonin Receptors
The binding of compounds of formula (I) to serotonin receptors was determined in vitro by standard methods. The preparations were investigated in accordance with the assays given hereinafter.
Method (a): For the binding to the 5-HT2C receptor the 5-HT2C receptors were radiolabeled with [3H]-5-HT. The affinity of the compounds for 5-HT2C receptors in a CHO cell line was determined according to the procedure of D. Hoyer, G. Engel and H. O. Kalkman, European J. Pharmacol., 1985, 118, 13-23.
Method (b): For the binding to the 5-HT2B receptor the 5-HT2B receptors were radiolabeled with [3H]-5-HT. The affinity of the compounds for human 5-HT2B receptors in a CHO cell line was determined according to the procedure of K. Schmuck, C. Ullmer, P. Engels and H. Lubbert, FEBS Lett., 1994, 342, 85-90.
Method (c): For the binding to the 5-HT2A receptor the 5-HT2A receptors were radiolabeled with [125I]-DOI. The affinity of the compounds for 5-HT2A receptors in a CHO cell line was determined according to the procedure of D. J. McKenna and S. J. Peroutka, J. Neurosci., 1989, 9, 3482-90.
Functional Activity
The functional activity of compounds of formula (I) was assayed using a Fluorimetric Imaging Plate reader (FLIPR). CHO cells expressing the human 5-HT2C or human 5-HT2A receptors were counted and plated into standard 96 well microtitre plates on the day before testing to give a confluent monolayer. The cells were then dye loaded with the calcium sensitive dye, Fluo-3-AM. Unincorporated dye was removed using an automated cell washer to leave a total volume of 100 xcexcL/well of assay buffer (Hanks balanced salt solution containing 20 mM Hepes and 2.5 mM probenecid). The drug (dissolved in 50 xcexcL of the assay buffer) was added at a rate of 70 xcexcL/sec to each well of the FLIPR 96 well plate during fluorescence measurements. The measurements were taken at 1 sec intervals and the maximum fluorescent signal was measured (approx 10-15 secs after drug addition) and compared with the response produced by 10 xcexcM 5-HT (defined as 100%) to which it was expressed as a percentage response (relative efficacy). Dose response curves were constructed using Graphpad Prism (Graph Software Inc.).
The compounds of formula (I) have activity at the h5-HT2c receptor in the range of 10,000 to 0.1 nM.